Axially Chiral Aryl-Alkene-Indole Framework: A Nascent Member of the Atropisomeric Family and Its Catalytic Asymmetric Construction

Article abstract of DOI:10.1002/cjoc.202000131

A new class of axially chiral aryl-alkene-indole frameworks have been designed, and the first catalytic asymmetric construction of such scaffolds has been established by the strategy of organocatalytic (Z/E)-selective and enantioselective (4+3) cyclization of 3-alkynyl-2-indolylmethanols with 2-naphthols or phenols (all >95 : 5 E/Z, up to 98% yield, 97% ee). This reaction also represents the first catalytic asymmetric construction of axially chiral alkene-heteroaryl scaffolds, which will add a new member to the atropisomeric family. This approach has not only confronted the great challenges in constructing axially chiral alkene-heteroaryl scaffolds but also provided a powerful strategy for the enantioselective construction of axially chiral aryl-alkene-indole frameworks.

Full text of DOI:10.1002/cjoc.202000131

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Axially Chiral Aryl-Alkene-Indole Framework: A Nascent Member of the
Atropisomeric Family and Its Catalytic Asymmetric Construction
Authors: Cong-Shuai Wang, Tian-Zhen Li, Si-Jia Liu, Yu-Chen Zhang, Shuang Deng,
Yinchun Jiao,* and Feng Shi*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000131.
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published online in Early View: http://dx.doi.org/10.1002/cjoc.202000131.
ISSN 1001-604X • CN 31-1547/O6
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Axially Chiral Aryl-Alkene-Indole Framework: A Nascent Member of the
Atropisomeric Family and Its Catalytic Asymmetric Construction
Cong-Shuai Wang,+,a Tian-Zhen Li,+,a Si-Jia Liu,a Yu-Chen Zhang,a Shuang Deng,b Yinchun Jiao,*,b and Feng Shi*,a
a School of Chemistry and Materials Science, Jiangsu Normal University, Xuzhou, 221116, P. R. China.
b Key Laboratory of Theoretical Organic Chemistry and Functional Molecule, Ministry of Education, School of Chemistry and Chemical Engineering, Hunan
University of Science and Technology, Xiangtan, 411201, P. R. China
+These authors contributed equally to this work.
Summary of main observation and conclusion A new class of axially chiral aryl-alkene-indole frameworks has been designed, and the first catalytic
asymmetric construction of such scaffolds has been established by the strategy of organocatalytic (Z/E)-selective and enantioselective (4+3) cyclization of
3-alkynyl-2-indolylmethanols with 2-naphthols or phenols (all >95:5 E/Z, up to 98% yield, 97% ee). This reaction also represents the first catalytic
asymmetric construction of axially chiral alkene-heteroaryl scaffolds, which will add a new member to the atropisomeric family. This approach has not
only confronted the great challenges in constructing axially chiral alkene-heteroaryl scaffolds but also provided a powerful strategy for the
enantioselective construction of axially chiral aryl-alkene-indole frameworks.
frameworks
Background and Originality Content
Axial chirality is one important feature of nature because axially
chiral frameworks constitute the core structures of many natural
products,[1] pharmaceutically relevant molecules[2] and chiral
ligands or catalysts.[3] In this context, the catalytic asymmetric
construction of axially chiral frameworks has received intensive
attention from scientists,[4-5] and many elegant approaches have
been developed for the enantioselective construction of axially
chiral biaryl[6-9] and heterobiaryl[10-11] frameworks, which have
become the majority of the axially chiral frameworks (Scheme 1a).
However, in sharp contrast, axially chiral alkene-arenes, as an
important class of atropisomers, have rarely been investigated.[12]
This is because the catalytic asymmetric construction of axially
chiral alkene-arene frameworks is much more challenging than
the construction of axially chiral biaryls due to the low rotational
barriers, low configurational stability and difficulty in controlling
the (E/Z)-selectivity and enantioselectivity.[13-14] As a result, there
are only limited examples on the catalytic asymmetric
construction of axially chiral alkene-arene frameworks, and all of
these structures are confined to axially chiral styrene derivatives
(Scheme 1b).[13-14] For example, the groups of Yan and Tan utilized
the strategy of organocatalytic addition reactions to vinylidene
ortho-quinone methides (VQMs).[14c-14e] In the presence of a chiral
base or acid, 2-ethynylphenol derivatives underwent a prototropic
rearrangement to give highly active VQM intermediates, which
were readily attacked by nucleophiles such as sulfinate anion,
benzenesulfonic acid and naphthols to afford axially chiral styrene
derivatives.
In contrast, axially chiral alkene-heteroaryl frameworks have
scarcely been discovered in the literature,[15] and the catalytic
asymmetric construction of such frameworks is an unknown
chemistry, which is challenging because the rotational barrier and
conformational stability of heteroaryl scaffolds, especially
five-membered scaffolds, are much lower than those of
six-membered aryls such as phenyl and naphthyl.[4g-4h] Therefore,
Indole-based axially chiral skeletons have recently attracted
it has become an urgent task to design a new class of axially chiral
increasing attention from chemists due to the unique properties
alkene-heteroaryl frameworks and develop innovative methods
of the indole ring and the importance of axially chiral
for the catalytic asymmetric construction of such frameworks.
indole-containing scaffolds.[16-17] To fulfill the above-mentioned
Scheme 1 Profile of catalytic asymmetric construction of axially chiral
task, we designed alkene-indoles as a new class of axially chiral
frameworks and design of a new class of axially chiral alkene-heteroaryl
*E-mail: fshi@jsnu.edu.cn; yinchunjiao@hnust.edu.cn
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Wang et al.
Report
alkene-heteroaryl frameworks (Scheme 1c). Nevertheless, there
are great challenges in the catalytic asymmetric construction of
axially chiral alkene-indole frameworks. For example, it is well
known that both axially chiral alkenes and five-membered biaryls
have low rotational barriers.[4g-4h,13-14] Accordingly, the integration
of an alkene group with a five-membered indole ring will make
the rotational barrier of alkene-indole frameworks extremely low,
which will result in the very low configurational stability of such
skeletons. Hence, it is a formidable challenge to hinder free
rotation around the axis and generate the axial chirality of the
alkene-indole framework. More importantly, even if the axial
chirality of alkene-indole frameworks can be generated, how to
construct such skeletons in a catalytic asymmetric manner and
how to control the (E/Z)-selectivity as well as the
enantioselectivity of the alkene-indole structures remain
enormous challenges.
(Scheme 3). In the design of the 3-alkynyl-2-indolylmethanols, the
t-Bu group was selected as a terminal bulky group for the alkyne
functionality, which will generate steric congestion around the
axis. In addition, the installation of two aromatic groups at the
benzylic position of the 2-indolylmethanols will increase the
reactivity of such reactants by stabilizing the carbocation
intermediate. These structural features will make this class of
3-alkynyl-2-indolylmethanols act as competent 1,4-dielectrophiles.
In the design of the reaction, the selection of 2-naphthols or
phenols as reactive 1,3-dinucleophiles is based on the
consideration that these reactants can easily be activated by CPA
to
perform
two
nucleophilic
additions
on
3-alkynyl-2-indolylmethanols, thus accomplishing the (4+3)
cyclization to construct the axially chiral aryl-alkene-indole
framework. CPA is a suitable B*-H because CPA can generate
hydrogen-bonding or ion-pairing interactions with the two
reaction partners, therefore controlling the regioselectivity,
(Z/E)-selectivity and enantioselectivity of the reaction.
To confront these challenges, we conceived a strategy for the
catalytic asymmetric construction of axially chiral alkene-indole
frameworks and avoiding free rotation around the axis (Scheme 2).
Indolylmethanols have proven to be versatile reactants for
constructing indole-containing scaffolds,[18-19] and based on our
experience with indolylmethanols,[16c,17a,20] we envision that
3-alkynyl-2-indolylmethanols as a new class of indolylmethanols
can serve as building blocks for constructing alkene-indole
frameworks. In detail, the incorporation of an alkyne functionality
Scheme 3 Design of catalytic asymmetric (4+3) cyclizations to construct
axially chiral aryl-alkene-indole frameworks
bearing
a bulky terminal R group in the structure of
2-indolylmethanol generates the desired C=C bond when using a
nucleophile to attack the alkynyl group. In principle, in the
presence
of
a
chiral
Brønsted
acid
(B-H*),
3-alkynyl-2-indolylmethanols should act as 1,4-dielectrophiles
that can be attacked by nucleophiles. When cyclic dinucleophiles
are employed as reaction partners, a (4+n) cyclization will occur to
construct the alkene-indole framework with axial chirality. This is
because the steric congestion between the R group and the H
atom as well as the constructed cyclic framework will lead to
hindered rotation around the alkene-indole axis, thus avoiding the
free rotation around the axis and generating the axial chirality of
the alkene-indole framework. Although this strategy seems
feasible, some challenging issues still remain, including (1) the
design and synthesis of 3-alkynyl-2-indolylmethanols bearing
suitable R/R1 groups to act as competent 1,4-dielectrophiles; (2)
the selection of reactive dinucleophiles that can be easily
activated by B*-H; and (3) controlling the regioselectivity of
nucleophilic addition, the (Z/E)-selectivity of the generated alkene
geometry and the enantioselectivity of the axially chiral
alkene-indole framework.
Herein, we report the design of a new class of axially chiral
aryl-alkene-indole frameworks and the first catalytic asymmetric
construction of such scaffolds by the strategy of organocatalytic
(Z/E)-selective and enantioselective (4+3) cyclization of
3-alkynyl-2-indolylmethanols with 2-naphthols or phenols
(all >95:5 E/Z, up to 98% yield, 97% ee).
Results and Discussion
Scheme
2 Our strategy for constructing axially chiral alkene-indole
Initially, the reaction of 3-alkynyl-2-indolylmethanol 1a with
2-naphthol 2a was employed to test the possibility of our design
(Table 1). Gratifyingly, under the catalysis of CPA 4a in toluene at
10 °C, the designed (4+3) cyclization smoothly occurred to give
axially chiral aryl-alkene-indole product 3aa in a high yield of 87%
and a good enantioselectivity of 86% ee (entry 1). The screening
of BINOL-derived CPA 4 (entries 1-7) revealed that CPA 4b could
catalyze the reaction with the highest enantioselectivity (entry 2).
Changing the backbone of CPA 4b to H8-BINOL and SPINOL
(entries 8-9) led to the discovery that H8-BINOL-derived CPA 5a
was the best catalyst, which promoted the reaction with a higher
enantioselectivity of 93% ee (entry 8). The subsequent evaluation
of solvents (entries 8 and 10-12) found that the reaction could
only occur in toluene and dichloroethane (entries 8 and 10), and
toluene was better than dichloroethane in terms of controlling
the reactivity and enantioselectivity. The variation in reaction
temperature (entries 8 and 13-15) indicated that 30 °C was a more
suitable reaction temperature than 10 °C with regard to the yield
(entry 14 vs 8). Finally, slightly modulating the molar ratio of the
frameworks
To address these challenging issues, we designed a chiral
phosphoric acid[21] (CPA)-catalyzed asymmetric (4+3) cyclization of
3-alkynyl-2-indolylmethanols with 2-naphthols or phenols
2
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Chin. J. Chem.
Table 2 Substrate scope of 3-alkynyl-2-indolylmethanols 1a
reactants (entries 16-18) led to the optimal reaction conditions
(entry 17), which could offer axially chiral product 3aa in a high
yield of 97% and an excellent enantioselectivity of 95% ee.
Notably, in all cases, only the (E)-isomer of 3aa was observed,
which implied that this reaction had a complete (E/Z)-selectivity.
Table 1 Optimization of reaction conditionsa
yield
(%)b
97
ee
(%)d
95
91
90
94
91
89
90
89
93
90
94
90
entry
R/Ar (1)
3
E/Zc
1
2
H/Ph (1a)
5-Me/Ph (1b)
5-OMe/Ph (1c)
5-Cl/Ph (1d)
3aa
3ba
3ca
3da
3ea
3fa
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
69
3
56
4
96
5
6e
5-Br/Ph (1e)
87
6-Cl/Ph (1f)
87
entry
1
Cat.
4a
4b
4c
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
T (°C)
10
10
10
10
10
10
10
10
10
10
10
10
-10
30
50
30
30
30
yield (%)b
87
ee (%)c
86
88
-
7
H/m-MeC6H4 (1g)
H/m-ClC6H4 (1h)
H/p-MeC6H4 (1i)
H/p-t-BuC6H4 (1j)
H/p-FC6H4 (1k)
H/p-ClC6H4 (1l)
3ga
3ha
3ia
72
8
61
2
88
9
64
3
trace
69
10
11
12
3ja
42
4
4d
4e
4f
87
-
3ka
3la
83
5
trace
trace
trace
91
52
6
-
aUnless otherwise indicated, the reaction was carried out on a 0.1 mmol
scale in toluene (1 mL) at 30 °C for 12 h, and the molar ratio of 1:2a was
1.2:1. bIsolated yield. cThe E/Z ratio was determined by 1H NMR. dThe
7
4g
5a
6a
5a
5a
5a
5a
5a
5a
5a
5a
5a
-
8
93
50
77
-
e
enantiomeric excess (ee) was determined by HPLC. Catalyzed by 40 mol%
(S)-5a.
9
44
10
11
12
13
14
15
16d
17e
18f
69
Then, the generality of the 2-naphthols 2 for the construction
of the axially chiral aryl-alkene-indole frameworks was examined.
As shown in Table 3, a wide range of 2-naphthols 2 bearing either
electron-donating or electron-withdrawing groups at different
positions could serve as competent reaction partners to undergo
EtOAc
N.R.
N.R.
62
CH3CN
-
toluene
toluene
toluene
toluene
toluene
toluene
87
93
76
88
95
93
the
catalytic
asymmetric
(4+3)
cyclization
with
96
3-alkynyl-2-indolylmethanol 1a, constructing the axially chiral
aryl-alkene-indole scaffolds 3 in overall good yield, complete (E/Z)
selectivity and high enantioselectivity.
99
90
97
Table 3 Substrate scope of 2-naphthols 2a
99
aUnless otherwise indicated, the reaction was carried out on a 0.1 mmol
scale and catalyzed by 10 mol% 4-6 in solvent (1 mL) for 12 h, and the
b
molar ratio of 1a:2a was 1:1.2. Isolated yield and only the (E)-isomer was
observed in all cases. cThe ee value was determined by HPLC. dThe molar
ratio of 1a:2a was 1:2. eThe molar ratio of 1a:2a was 1.2:1. fThe molar ratio
of 1a:2a was 2:1. DCE = ClCH2CH2Cl. N.R. = No reaction.
yield
(%)b
98
ee
(%)d
93
entry
R (2)
3
E/Zc
With the optimal reaction conditions known, we then studied
the substrate scope of 3-alkynyl-2-indolylmethanols 1 for the
construction of axially chiral aryl-alkene-indole frameworks. As
listed in Table 2, this catalytic asymmetric (4+3) cyclization was
amenable to a series of 3-alkynyl-2-indolylmethanols 1 with
various R/Ar substituents at different positions, which gave rise to
the axially chiral aryl-alkene-indole derivatives 3 in moderate to
1
2
6-Me (2b)
6-Et (2c)
3ab
3ac
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
75
94
3
6-OMe (2d)
6-Br (2e)
3ad
64
91
4
5e
3ae
74
92
high
yield,
perfect
(E/Z)-selectivity
and
excellent
enantioselectivity.
6-CN (2f)
ent-3af
3ag
76
91
6
6-p-OMeC6H4 (2g)
68
97
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3

Wang et al.
Report
3-alkynyl-2-indolylmethanols, which might play an important role
in stabilizing the carbocation intermediate (see page S190 of the
Supporting Information for theoretical calculations). Therefore,
these control experiments verified the structural features
necessary when we began to design this new class of
indolylmethanols for constructing axially chiral alkene-indole
frameworks.
7
8f
9g
10
11
12
7-OMe (2h)
7-Br (2i)
3ah
3ai
84
79
80
97
65
55
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
90
90
89
94
94
91
7-I (2j)
3aj
7-p-OMeC6H4 (2k)
7-Ph (2l)
3ak
3al
8-F (2m)
3am
Scheme 4 Control experiments
aUnless otherwise indicated, the reaction was carried out on a 0.1 mmol
scale in toluene (1 mL) at 30 °C for 12 h, and the molar ratio of 1a:2 was
1.2:1. bIsolated yield. cThe E/Z ratio was determined by 1H NMR. dThe
enantiomeric excess (ee) was determined by HPLC. eThe reaction was
f
catalyzed by 30 mol% (R)-5a. The absolute configuration of product 3ai
was determined to be (S) by single crystal X-ray diffraction analysis after
recrystallization.[22] gCatalyzed by 40 mol% (S)-5a.
Apart from the 2-naphthols, several phenols 7 can also act as
suitable 1,3-dinucleophiles to perform the catalytic asymmetric
(4+3) cyclization with 3-alkynyl-2-indolylmethanols (Table 4),
which afforded axially chiral aryl-alkene-indole derivatives 8 in
acceptable yield, perfect (E/Z)-selectivity and excellent
enantioselectivity.
Table 4 Utilizing phenols 7 as substrates for the construction of axially
chiral aryl-alkene-indole frameworksa
From the point of the reaction mechanism, the (4+3) cyclization
involves two nucleophilic additions of the 1,3-dinucleophile to the
3-alkynyl-2-indolylmethanol. Therefore, in principle, there are two
possible reaction pathways based on different sequences of the
two nucleophilic additions. To better understand the reaction
pathways and find the more possible one, we performed DFT
calculations on the reaction and found two possible reaction
pathways, A and B (Schemes 5 and 6), for the CPA-catalyzed (4+3)
cyclization of 3-alkynyl-2-indolylmethanol 1a with 2-naphthol 2i
(see page S132 of the Supporting Information) based on the
previously reported theoretical calculations of CPA-catalyzed
reactions.[23]
aUnless otherwise indicated, the reaction was carried out on a 0.1 mmol
scale in toluene (1 mL) with MgSO4 (100 mg) at 30 °C for 12 h, and the
molar ratio of 1:7 was 4:1. The yield refers to the isolated yield. The E/Z
ratio was determined by 1H NMR, and the ee value was determined by
HPLC. bThe molar ratio of 1:7 was 1.2:1 for 24 h. cThe molar ratio of 1e:7c
was 2:1.
In
possible
reaction
pathway
A
(Scheme
5),
3-alkynyl-2-indolylmethanol 1a is suggested to transform into
allene-iminium intermediate I via a transition state (TS-1) with an
energy barrier of 10.51 kcal mol-1. Then, the CPA anion
simultaneously activates both 2-naphthol 2i and intermediate I by
hydrogen-bonding and ion-pairing interactions to promote the
nucleophilic addition between them (TS-2), thus generating
intermediate II with axial chirality. Intermediate II can easily
isomerize into another intermediate, III, via TS-3 with a low
energy barrier of 6.51 kcal mol-1 due to the force of
rearomatization of the naphthol ring. Subsequently, CPA forms
two hydrogen bonds with the two OH groups of intermediate III
(TS-4) to generate carbocation intermediate IV via dehydration.
Finally, activated again by the CPA anion, the intramolecular
nucleophilic addition of intermediate IV (TS-5) gives rise to axially
chiral product 3ai with the regeneration of the CPA catalyst.
To gain some insights into the catalytic asymmetric (4+3)
cyclization, we performed some control experiments (Scheme 4).
First, to investigate the possible activation mode of the chiral
phosphoric acid on the two substrates, we employed the
O-methyl-protected substrate 2n and N-methyl-protected
substrate 1m for the reaction under standard conditions (Scheme
4a). In both cases, no reaction occurred, and no one-step addition
reaction to the alkynyl group of substrates 1 was observed. These
results demonstrated that the OH group of substrates 2 and the
NH group of substrates 1 played a crucial role in promoting the
reaction, which might form hydrogen-bonding interactions with
CPA during the reaction process. Second, to study the role of the
diaryl groups in 3-alkynyl-2-indolylmethanols, substrates 1n and
1o, bearing two aliphatic groups, were engaged in the reaction,
and no reaction occurred (Scheme 4b). This outcome indicated
that the two aromatic groups at the benzylic position are
necessary
for
the
high
reactivity
of
the
4
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Scheme 5 Possible reaction pathway A and calculated free energy profile
(see page S134 of the Supporting Information for detailed
The theoretical calculations rationalized our observations on
the control experiments in Scheme 4. Namely, the OH group in
substrates 2 and the NH group in substrates 1 could form
hydrogen-bonding and ion-pairing interactions with CPA during
the reaction process. In addition, the two aromatic groups at the
benzylic position of 3-alkynyl-2-indolylmethanols 1 would stabilize
the carbocation in intermediate IV, which is crucial for the
reactivity of this new class of indolylmethanols. Overall, the
calculated free energy profile of possible reaction pathway A is
reasonable and feasible, which could explain the chemistry of the
catalytic asymmetric (4+3) cyclization. Moreover, additional
theoretical calculations and experiments also supported the role
of the two aryl groups at the benzylic position and the possible
reaction pathway A (see page S190 of the Supporting Information
for details).
discussion). Therefore, these calculation results suggest that
reaction pathway A has a higher probability than reaction
pathway B.
However, in possible reaction pathway B (Scheme 6), the free
energies of some steps are much higher than those in pathway A
Chin. J. Chem. 2018, template
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5

Scheme 6 Possible reaction pathway B and calculated free energy profile
atropisomers.[1f] Therefore, these results verified the formidable
To better understand the conformational stability of this new
class of axially chiral aryl-alkene-indole scaffolds, we performed
racemization studies on representative aryl-alkene-indoles 3aa
and 3da (see page S38 of the Supporting Information for details).
First, we investigated the effect of temperature on the
racemization of 3aa and 3da (Scheme 7a), which indicated that
this class of axially chiral aryl-alkene-indole scaffolds underwent
the racemization process slowly at 40 °C or 50 °C. Second, we
experimentally calculated the racemization barriers of 3aa and
3da (Scheme 7b). It was found that their racemization barriers
(28.0 kcal mol-1) are just slightly greater than 24 kcal mol-1, which
is the required racemization barrier for isolating the individual
challenges in generating the axial chirality of aryl-alkene-indole
frameworks due to the extremely low racemization barrier and
the very low configurational stability of such skeletons. More
importantly, the efficient control of the (Z/E)-selectivity and the
enantioselectivity of products 3 manifested the superiority of our
strategy for constructing axially chiral aryl-alkene-indole
frameworks.
Chin. J. Chem. 2018, template
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6

Chin. J. Chem.
Scheme
scaffolds
7
Racemization studies on axially chiral aryl-alkene-indole
Finally, to investigate the potential bioactivity of this class of
axially chiral aryl-alkene-indoles, compound 3ka was subjected to
the evaluation of its cytotoxicity (Scheme 9, see page S41 of the
Supporting Information for details). This compound displayed
potent cytotoxicity toward several cancer cell lines, with IC50
values ranging from 39.29 to 50.85 μg mL-1, which implied that
this class of axially chiral aryl-alkene-indoles is promising to
discover an application in medicinal chemistry.
Scheme 9 Cytotoxicity of the axially chiral product 3ka
Conclusions
In summary, we have accomplished the design of a new class
of axially chiral aryl-alkene-indole frameworks and the first
catalytic asymmetric construction of such scaffolds by the strategy
of organocatalytic (Z/E)-selective and enantioselective (4+3)
cyclization of 3-alkynyl-2-indolylmethanols with 2-naphthols or
phenols (all >95:5 E/Z, up to 98% yield, 97% ee). This reaction also
represents the first catalytic asymmetric construction of axially
chiral alkene-heteroaryl scaffolds, which will add a new member
to the atropisomeric family. This approach has not only
confronted the great challenges in constructing axially chiral
alkene-heteroaryl scaffolds but also provided a powerful strategy
for the construction of axially chiral aryl-alkene-indole frameworks
in an enantioselective manner. In addition, this approach has
realized the design and synthesis of 3-alkynyl-2-indolylmethanols
as a new kind of indolylmethanols and has accomplished the first
application of such reactants in catalytic asymmetric reactions.
This reaction will not only contribute greatly to the chemistry of
axial chirality and indolylmethanols but also serve as a robust
protocol for constructing seven-membered heterocycles bearing
axial chirality.
In addition, one millimole scale synthesis of axially chiral
aryl-alkene-indoles 3ae and 3ah demonstrated that this reaction
could be scaled up (Scheme 8a). Moreover, product 3aj can be
derived into compounds 9-12 with retained excellent
(E/Z)-selectivity and good enantioselectivity (Scheme 8b).
Scheme 8 One millimole scale reactions and derivation of product 3aj
Experimental
General Procedure for the synthesis of products 3:
To the mixture of 3-alkynyl-2-indolylmethanol 1 (0.12 mmol),
2-naphthol 2 (0.1 mmol), catalyst (S)-5a (6.1 mg, 0.01 mmol) was
added toluene (1 mL). Then, the reaction mixture was stirred at
o
30 C for 12 h. After the completion of the reaction which was
indicated by TLC, the reaction mixture was directly purified
through preparative thin layer chromatography on silica gel to
afford pure product 3.
General Procedure for the synthesis of products 8:
To the mixture of 3-alkynyl-2-indolylmethanol 1 (0.4 mmol),
phenol 7 (0.1 mmol), MgSO4 (100 mg), catalyst (S)-5a (18.3 mg,
0.03 mmol) was added toluene (1 mL). Then, the reaction mixture
was stirred at 30 oC for 12 h. After the completion of the reaction
which was indicated by TLC, the reaction mixture was directly
purified through preparative thin layer chromatography on silica
gel to afford pure product 8.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Chin. J. Chem. 2020, 38, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
This article is protected by copyright. All rights reserved.
www.cjc.wiley-vch.de
7

Wang et al.
Report
Zhang, S.; Liao, G.; Shi, B.-F. Enantioselective Synthesis of
Atropisomers Featuring Pentatomic Heteroaromatics. Chin. J. Org.
Chem. 2019, 39, 1522–1528 (in Chinese).
Acknowledgement
We are grateful for financial support from NSFC (21772069
and 21831007), and Six Kinds of Talents Project of Jiangsu
Province (SWYY-025). We sincerely appreciate Prof. Shu Zhang for
her help in biological evaluations.
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Enantiodivergent Atroposelective Synthesis of Chiral Biaryls by
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8
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© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2020, 38, XXX－XXX
This article is protected by copyright. All rights reserved.

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© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
This article is protected by copyright. All rights reserved.
www.cjc.wiley-vch.de
9

Wang et al.
Report
Liu, Y.; Deng, J.; Yan, H. Organocatalytic Enantioselective
10.1002/cjoc.202000022.
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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2020
Manuscript revised: XXXX, 2020
Manuscript accepted: XXXX, 2020
Accepted manuscript online: XXXX, 2020
Version of record online: XXXX, 2020
The
Cambridge
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Page No.
Axially Chiral Aryl-Alkene-Indole Framework: A
Nascent Member of the Atropisomeric Family
and Its Catalytic Asymmetric Construction
Cong-Shuai Wang, Tian-Zhen Li, Si-Jia Liu,
Yu-Chen Zhang, Shuang Deng, Yinchun Jiao* and
Feng Shi*
The first catalytic asymmetric construction of axially chiral aryl-alkene-indole scaffolds has been
established by (4+3) cyclization of 3-alkynyl-2-indolylmethanols with 2-naphthols or phenols.
12
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© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2020, 38, XXX－XXX
This article is protected by copyright. All rights reserved.